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Energy requirements for the Na⁺ gradient in the oxygenated isolated heart: effect of changing the free energy of ATP hydrolysis

²Division of Cardiovascular Disease, Department of Medicine, University of Alabama, Birmingham, Alabama 35294-4470; and ¹NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Department of Medicine Brigham Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Submitted 11 June 2003 ; accepted in final form 19 August 2003

This study tests the hypothesis that a decrease of the free energy of ATP hydrolysis (G_ATP) below a threshold value will inhibit Na⁺-K⁺-ATPase (Na⁺ pump) activity and result in an increase of intracellular Na⁺ concentration ([Na⁺]_i) in the heart. Conditions were designed in which hearts were solely dependent on ATP derived from oxidative phosphorylation. The only substrate supplied was the fatty acid butyrate (Bu) at either low, 0.1 mM (LowBu), or high, 4 mM (HighBu), concentrations. Escalating work demand reduced the G_ATP of the LowBu hearts. ³¹P, ²³Na, and ⁸⁷Rb NMR spectroscopy measured high-energy phosphate metabolites, [Na⁺]_i, and Rb⁺ uptake. Rb⁺ uptake was used to estimate Na⁺ pump activity. To measure [Na⁺]_i using a shift reagent for cations, extracellular Ca²⁺ was reduced to 0.85 mM, which eliminated work demand G_ATP reductions. Increasing extracellular Na⁺ () to 200 mM restored work demand G_ATP reductions. In response to higher [Na⁺]_e, [Na⁺]_i increased equally in LowBu and HighBu hearts to 8.6 mM, but G_ATP decreased only in LowBu hearts. At lowest work demand the LowBu heart G_ATP was –53 kJ/mol, Rb⁺ uptake was similar to that of HighBu hearts, and [Na⁺]_i was constant. At highest work demand the LowBu heart G_ATP decreased to –48 kJ/mol, the [Na⁺]_i increased to 25 mM, and Rb⁺ uptake was 56% of that in HighBu hearts. At the highest work demand the HighBu heart G_ATP was –54 kJ/mol and [Na⁺]_i increased only 10%. We conclude that a G_ATP below –50 kJ/mol limits the Na⁺ pump and prevents maintenance of [Na⁺]_i homeostasis.

energy metabolism; intracellular sodium

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